The invention pertains to the field of treatment of proliferative diseases and especially the treatment of vascular diseases such as, for example, arteriosclerosis.
It is known that ionizing radiation inhibits the proliferation of cells. A considerable number of neoplastic and non-neoplastic diseases have already been treated in this way (Fletcher, Textbook of Radiotherapy, Philadelphia, Pa.: Lea and Febiger, 1980, Hall, Radiobiology for the Radiologist, Philadelphia, Pa.: Lippincott, 1988).
An attempt has also already been made to treat arteriosclerotic diseases using this process. Arteriosclerosis is an inflammatory, fibroproliferative disease that is responsible for 50% of all deaths in the USA, Europe, and Japan (Ross 1993, Nature 362: 801-809). In its peripheral manifestation, it threatens the upkeep of the extremities; with its coronary manifestation, the risk of fatal myocardial infarction exists; and with supra-aortic infection, there is the threat of stroke.
At this time, arteriosclerosis is treated in various ways. In addition to conservative measures (e.g., lowering the cholesterol level in the blood) and the bypass operation, mechanical dilatation (angioplasty), as well as the intravascular removal of atheromatous tissue (atherectomy) of stenotic segments in peripheral arteries and the coronaries have been established as alternatives in regular clinical practice.
As stated below, the above-mentioned methods are associated with a considerable number of drawbacks, however.
The value of mechanical recanalization processes is greatly diminished by vascular occlusions as a result of vascular tears and dissections, as well as acute thromboses (Sigwart et al. 1987, N. Engl. J. Med. 316: 701-706). Long-term success is jeopardized by the reoccurrence of constrictions (restenosis). The CAVEAT study thus revealed that of 1012 patients, the restenosis rate six months after intervention in coronary atherectomy was 50% and in coronary angioplasty even 57% (Topol et al. 1993, N. Engl. J. Med. 329: 221-227). In addition, abrupt vascular occlusion occurred in this study in 7% of the atherectomy patients and in 3% of the angioplasty patients. Nicolini and Pepine (1992, Endovascular Surgery 72: 919-940) report a restenosis rate of between 35 and 40% and an acute occlusion rate of 4% after angioplastic intervention.
To combat these complications, various techniques have been developed. These include the implantation of metal endoprostheses (stents), (Sigwart et al. 1987, N. Engl. J. Med. 316: 701-706; Strecker et al., 1990, Radiology 175: 97-102). The implantation of stents in large-caliber arteries, e.g., in occlusions in the axis in the pelvis, has already become a treatment modality that is to be applied primarily. The use of stents in femoral arteries has shown disappointing results, however, with a primary openness rate of 49% and a reocclusion frequency of 43% (Sapoval et al., 1992, Radiology 184: 833-839). Similar unsatisfactory results have been achieved with currently available stents in coronary arteries (Kavas et al. 1992, J. Am. Coll. Cardiol. 20: 467-474).
Up until now, no pharmacological or mechanical interventions have been able to prevent restenosis (Muller et al. 1992, J. Am. Coll. Cardiol. 19: 418-432, Popma et al. 1991, Circulation 84: 14226-1436).
The reason for the restenoses frequently occurring after mechanical intervention is assumed to be that interventions induce a proliferation and migration of unstriped muscle cells in the vascular wall. The latter result in a neointimal hyperplasia and the observed restenoses in the treated vessel sections (Cascells 1992, Circulation 86, 723-729, Hanke et al. 1990, Circ. Res. 67, 651-659, Ross 1986, Nature 362, 801-809, Ross 1993, Nature 362, 801-809).
An alternative process for treating arteriosclerotic diseases uses ionizing radiation. The use of ionizing radiation of external origin on restenosis is associated with the drawback, however, that upon administration the radiation dose is not limited just to the desired spot; rather, the surrounding (healthy) tissue is also undesirably exposed to the radiation. Thus, to date, various studies have come up with little to increase the chances of success (Gellmann et al. 1991, Circulation 84 Suppl. II: 46A-59A, Schwartz et al. 1992, J. Am. Coll. Cardiol. 19: 1106-1113).
These drawbacks, which occur when external radiation sources are used, can be overcome if gamma radiation is directly used with restenosis via, e.g., a catheter in the vascular area. With this form of administration with iridium-192, a high radiation dose of 20 Gy is applied to the restenosis foci. Some works report on the almost complete prevention of restenosis after this intervention (Wiedermann et al. 1994, Am. J. Physiol. 267: H125-H132, Bxc3x6ttcher et al. 1994, Int. J. Radiation Oncology Biol. Phys. 29: 183-186, Wiedermann et al. 1994 , J. Am. Coll. Cardiol. 23: 1491-1498, Liermann et al. 1994, Cardiovasc. Intervent. Radiol. 17: 12-16). A drawback to this method is, however, that the radiation dose of 20 Gy that is applied in this case is very high. Since the lesions are dispersed irregularly on the vascular wall, uniform administration of a defined dose is not possible using this technique. Moreover, treatment of large-caliber vessels is not possible since, because of the dose reduction from the iridium source, the dose that can be administered is not adequate.
Another possible way of inhibiting restenosis is the implantation of P-32-doped stents (Fischell et al. Stents III, Entwicklung, Indikationen und Zukunft, Konstanz [Development, Indications, and the Future: Constancy]: Kollath and Liermann, 1995). In this work, an activity of 0.2 kBq P-32 per centimeter of stent length was enough (corresponding to a radiation dose of 0.25 Gy) to achieve maximum inhibition of unstriped vascular muscle cells in vitro. It was thus possible to show that not only xcex3-emitters but also xcex2-emitters prevent the proliferation of unstriped muscle cells. An advantage of this method is that the radiation dose administered is considerably lower than in all previously mentioned interventions. At this low dose, the endothelial cells that line the vascular bed are not damaged (Fischell et al. Stents III, Entwicklung, Indikationen und Zukunft, Konstanz: Kollath and Liermann, 1995). This form of intervention can be used only once, however, namely when the stent is positioned. In addition, it is limited only to those interventions in which stents are used. The restenoses that occur in the far more common types of interventions, such as atherectomies and angioplasties, cannot be treated with this method. Because of the small range of action of the xcex2-radiation, it is not possible to administer a uniform dose of energy to the entire lesion.
In addition to radiation therapy, a number of other therapeutic strategies are used for inhibiting neointimal hyperplasias (restenoses). The latter comprise standard medicines for suppression of restenoses such as antithrombotic agents, platelet aggregation inhibitors, calcium antagonists, anti-inflammatory and antiproliferative substances, but also gene-therapy approaches. In this case, the inhibition of growth stimulators, e.g., by antisense oligonucleotides or the enhancement of inhibiting factors by expression-vector-plasmids and the virus-mediated gene integration, is possible. Also, Aptamer oligonucleotides can be used for inhibiting a wide variety of receptor-mediated processes, which play a decisive role in restenosis.
With great energy and care, substances have been studied over the years that were administered under strictly controlled conditions as a long-term treatment since the desired purpose was theoretically to reduce the restenosis rate (Herrmann et al., 1993, Drugs 46: 18-52).
More than 50 controlled studies with different substance groups were performed, without yielding definite proof that the substances examined could seriously reduce the restenosis rate.
This also applies for topical administration, in which the substances are brought via a special balloon catheter to the site of action that is desired in each case. It has been shown, however, that the previously used substances are washed too quickly from the vascular wall to be able to be therapeutically effective. Moreover, additional vascular wall alterations, which even act to promote restenosis, are induced by these pressure-mediated liquid injections.